Mitochondria-mediated apoptosis in mammals

Abstract

The mitochondria-mediated caspase activation pathway is a major apoptotic pathway characterized by mitochondrial outer membrane permeabilization (MOMP) and subsequent release of cytochrome c into the cytoplasm to activate caspases. MOMP is regulated by the Bcl-2 family of proteins. This pathway plays important roles not only in normal development, maintenance of tissue homeostasis and the regulation of immune system, but also in human diseases such as immune disorders, neurodegeneration and cancer. In the past decades the molecular basis of this pathway and the regulatory mechanism have been comprehensively studied, yet a great deal of new evidence indicates that cytochrome c release from mitochondria does not always lead to irreversible cell death, and that caspase activation can also have non-death functions. Thus, many unsolved questions and new challenges are still remaining. Furthermore, the dysfunction of this pathway involved in cancer development is obvious, and targeting the pathway as a therapeutic strategy has been extensively explored, but the efficacy of the targeted therapies is still under development. In this review we will discuss the mitochondria-mediated apoptosis pathway and its physiological roles and therapeutic implications.

Keywords

apoptosome / Bcl-2 family / IAPs / IAP antagonists / cancer therapy

References

[1] Acehan D, Jiang X, Morgan DG, Heuser JE, Wang X, Akey CW (2002) Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation. Mol Cell9: 423-432

[2] Ackler S, Xiao Y, Mitten MJ, Foster K, Oleksijew A, Refici M, Schlessinger S, Wang B, Chemburkar SR, Bauch J (2008) ABT-263 and rapamycin act cooperatively to kill lymphoma cells in vitro and in vivo. Mol Cancer Ther7: 3265-3274

[3] Ashkenazi A, Holland P, Eckhardt SG (2008) Ligand-based targeting of apoptosis in cancer: the potential of recombinant human apoptosis ligand 2/Tumor necrosis factor-related apoptosisinducing ligand (rhApo2L/TRAIL). J Clin Oncol26: 3621-3630

[4] Bakhshi A, Jensen JP, Goldman P, Wright JJ, McBride OW, Epstein AL, Korsmeyer SJ (1985) Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell41: 899-906

[5] Barrett RM, Colnaghi R, Wheatley SP (2011) Threonine 48 in the BIR domain of survivin is critical to its mitotic and anti-apoptotic activities and can be phosphorylated by CK2 in vitro. Cell Cycle10: 538-548

[6] Ben-Ari Z, Pappo O, Cheporko Y, Yasovich N, Offen D, Shainberg A, Leshem D, Sulkes J, Vidne BA, Hochhauser E (2007) Bax ablation protects against hepatic ischemia/reperfusion injury in transgenic mice. Liver Transplant13: 1181-1188

[7] Beug ST, Cheung HH, Lacasse EC, Korneluk RG (2012) Modulation of immune signalling by inhibitors of apoptosis. Trends Immunol33(11): 535-545

[8] Bykov VJ, Issaeva N, Shilov A, Hultcrantz M, Pugacheva E, Chumakov P, Bergman J, Wiman KG, Selivanova G (2002) Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med8: 282-288

[9] Cao X, Yap JL, Newell-Rogers MK, Peddaboina C, Jiang W, Papaconstantinou HT, Jupitor D, Rai A, Jung KY, Tubin RP (2013) The novel BH3 alpha-helix mimetic JY-1-106 induces apoptosis in a subset of cancer cells (lung cancer, colon cancer and mesothelioma) by disrupting Bcl-xL and Mcl-1 protein-protein interactions with Bak. Mol Cancer12: 42

[10] Cecconi F, Alvarez-Bolado G, Meyer BI, Roth KA, Gruss P (1998) Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell94: 727-737

[11] Chai J, Du C, Wu JW, Kyin S, Wang X, Shi Y (2000) Structural and biochemical basis of apoptotic activation by Smac/DIABLO. Nature406: 855-862

[12] Chai J, Shiozaki E, Srinivasula SM, Wu Q, Datta P, Alnemri ES, Shi Y, Dataa P (2001) Structural basis of caspase-7 inhibition by XIAP. Cell104: 769-780

[13] Chan FK (2012) Fueling the flames: mammalian programmed necrosis in inflammatory diseases. Cold Spring Harb Perspect Biol4(11). doi:10.1101/cshperspect.a008805

[14] Chen DJ, Huerta S (2009) Smac mimetics as new cancer therapeutics. Anticancer Drugs20: 646-658

[15] Chen P, Nordstrom W, Gish B, Abrams JM (1996) Grim, a novel cell death gene in Drosophila. Genes Dev10: 1773-1782

[16] Chen R, Valencia I, Zhong F, McColl KS, Roderick HL, Bootman MD, Berridge MJ, Conway SJ, Holmes AB, Mignery GA (2004) Bcl-2 functionally interacts with inositol 1,4,5-trisphosphate receptors to regulate calcium release from the ER in response to inositol 1,4,5-trisphosphate. J cell biol166: 193-203

[17] Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T, Korsmeyer SJ (2001) BCL-2, BCL-X(L) sequester BH3 domainonly molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell8: 705-711

[18] Cho YS, Challa S, Moquin D, Genga R, Ray TD, Guildford M, Chan FK (2009) Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell137: 1112-1123

[19] Crook NE, Clem RJ, Miller LK (1993) An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif. J Virol67: 2168-2174

[20] Danial NN, Gramm CF, Scorrano L, Zhang CY, Krauss S, Ranger AM, Datta SR, Greenberg ME, Licklider LJ, Lowell BB (2003) BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature424: 952-956

[21] Danial NN, Gimenez-Cassina A, Tondera D (2010) Homeostatic functions of BCL-2 proteins beyond apoptosis. Adv Exp Med Biol687: 1-32

[22] Devarajan E, Sahin AA, Chen JS, Krishnamurthy RR, Aggarwal N, Brun AM, Sapino A, Zhang F, Sharma D, Yang XH (2002) Down-regulation of caspase 3 in breast cancer: a possible mechanism for chemoresistance. Oncogene21: 8843-8851

[23] Deveraux QL, Takahashi R, Salvesen GS, Reed JC (1997) X-linked IAP is a direct inhibitor of cell-death proteases. Nature388: 300-304

[24] Deveraux QL, Reed JC (1999) IAP family proteins-suppressors of apoptosis. Genes Dev13: 239-252

[25] Du C, Fang M, Li Y, Li L, Wang X (2000) Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell102: 33-42

[26] Dubrez L, Berthelet J, Glorian V (2013) IAP proteins as targets for drug development in oncology. Onco Targets Ther9: 1285-1304

[27] Edison N, Zuri D, Maniv I, Bornstein B, Lev T, Gottfried Y, Kemeny S, Garcia-Fernandez M, Kagan J, Larisch S (2012) The IAPantagonist ARTS initiates caspase activation upstream of cytochrome C and SMAC/Diablo. Cell Death Differ19: 356-368

[28] Ellis HM, Horvitz HR (1986) Genetic control of programmed cell death in the nematode C. elegans. Cell44: 817-829

[29] Endo K, Kohnoe S, Watanabe A, Tashiro H, Sakata H, Morita M, Kakeji Y, Maehara Y (2009) Clinical significance of Smac/ DIABLO expression in colorectal cancer. Oncol Rep21: 351-355

[30] Fischer U, Schulze-Osthoff K (2005) New approaches and therapeutics targeting apoptosis in disease. Pharmacol Rev57: 187-215

[31] Fulda S, Vucic D (2012) Targeting IAP proteins for therapeutic intervention in cancer. Nat Rev Drug Discov11: 109-124

[32] Fulda S, Wick W, Weller M, Debatin KM (2002) Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med8: 808-815

[33] Gao Z, Tian Y, Wang J, Yin Q, Wu H, Li YM, Jiang X (2007) A dimeric Smac/diablo peptide directly relieves caspase-3 inhibition by XIAP. Dynamic and cooperative regulation of XIAP by Smac/ Diablo. J Biol Chem282: 30718-30727

[34] Garcia-Fernandez M, Kissel H, Brown S, Gorenc T, Schile AJ, Rafii S, Larisch S, Steller H (2010) Sept4/ARTS is required for stem cell apoptosis and tumor suppression. Genes Dev24: 2282-2293

[35] Goldstein JC, Waterhouse NJ, Juin P, Evan GI, Green DR (2000) The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant. Nat Cell Biol2: 156-162

[36] Goldstein JC, Munoz-Pinedo C, Ricci JE, Adams SR, Kelekar A, Schuler M, Tsien RY, Green DR (2005) Cytochrome c is released in a single step during apoptosis. Cell Death Differ12: 453-462

[37] Gottfried Y, Rotem A, Lotan R, Steller H, Larisch S (2004) The mitochondrial ARTS protein promotes apoptosis through targeting XIAP. EMBO J23: 1627-1635

[38] Goyal L, McCall K, Agapite J, Hartwieg E, Steller H (2000) Induction of apoptosis by Drosophila reaper, hid and grim through inhibition of IAP function. EMBO J19: 589-597

[39] Grether ME, Abrams JM, Agapite J, White K, Steller H (1995) The head involution defective gene of Drosophila melanogaster functions in programmed cell death. Genes Dev9: 1694-1708

[40] Guicciardi ME, Gores GJ (2013) Unshackling caspase-7 for cancer therapy. J Clin Investig123: 3706-3708

[41] Hakem R, Hakem A, Duncan GS, Henderson JT, Woo M, Soengas MS, Elia A, de la Pompa JL, Kagi D, Khoo W (1998) Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell94: 339-352

[42] Han J, Zhong CQ, Zhang DW (2011) Programmed necrosis: backup to and competitor with apoptosis in the immune system. Nat Immunol12: 1143-1149

[43] Hao Y, Sekine K, Kawabata A, Nakamura H, Ishioka T, Ohata H, Katayama R, Hashimoto C, Zhang X, Noda T (2004) Apollon ubiquitinates SMAC and caspase-9, and has an essential cytoprotection function. Nat Cell Biol6: 849-860

[44] Hao Z, Duncan GS, Chang CC, Elia A, Fang M, Wakeham A, Okada H, Calzascia T, Jang Y, You-Ten A (2005) Specific ablation of the apoptotic functions of cytochrome C reveals a differential requirement for cytochrome C and Apaf-1 in apoptosis. Cell121: 579-591

[45] Hardwick JM, Soane L (2013) Multiple functions of BCL-2 family proteins. Cold Spring Harb Perspect Biol5(2). doi:10.1101/cshperspect.a008722

[46] Harlin H, Reffey SB, Duckett CS, Lindsten T, Thompson CB (2001) Characterization of XIAP-deficient mice. Mol Cell Biol21: 3604-3608

[47] He S, Wang L, Miao L, Wang T, Du F, Zhao L, Wang X (2009) Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell137: 1100-1111

[48] Hegde R, Srinivasula SM, Zhang Z, Wassell R, Mukattash R, Cilenti L, DuBois G, Lazebnik Y, Zervos AS, Fernandes-Alnemri T (2002) Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis proteincaspase interaction. J Biol Chem277: 432-438

[49] Herbst RS, Frankel SR (2004) Oblimersen sodium (Genasense bcl-2 antisense oligonucleotide): a rational therapeutic to enhance apoptosis in therapy of lung cancer. Clin Cancer Res10: 4245s-4248s

[50] Hetz C, Vitte PA, Bombrun A, Rostovtseva TK, Montessuit S, Hiver A, Schwarz MK, Church DJ, Korsmeyer SJ, Martinou JC (2005) Bax channel inhibitors prevent mitochondrion-mediated apoptosis and protect neurons in a model of global brain ischemia. J Biol Chem280: 42960-42970

[51] Hitomi J, Christofferson DE, Ng A, Yao J, Degterev A, XavierR J, Yuan J (2008) Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell135: 1311-1323

[52] Hockenbery D, Nunez G, Milliman C, Schreiber RD, Korsmeyer SJ (1990) Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature348: 334-336

[53] Horvitz HR (1999) Genetic control of programmed cell death in the nematode Caenorhabditis elegans. Cancer Res59: 1701s-1706s

[54] Horvitz HR, Shaham S, Hengartner MO (1994) The genetics of programmed cell death in the nematode Caenorhabditis elegans. Cold Spring Harb Symp Quant Biol59: 377-385

[55] Hu Y, Ding L, Spencer DM, Nunez G (1998) WD-40 repeat region regulates Apaf-1 self-association and procaspase-9 activation. J Biol Chem273: 33489-33494

[56] Huang Y, Park YC, Rich RL, Segal D, Myszka DG, Wu H (2001) Structural basis of caspase inhibition by XIAP: differential roles of the linker versus the BIR domain. Cell104: 781-790

[57] Huang H, Zhang XF, Zhou HJ, Xue YH, Dong QZ, Ye QH, Qin LX (2010) Expression and prognostic significance of osteopontin and caspase-3 in hepatocellular carcinoma patients after curative resection. Cancer Sci101: 1314-1319

[58] Jiang X, Wang X (2000) Cytochrome c promotes caspase-9 activation by inducing nucleotide binding to Apaf-1. J Biol Chem275: 31199-31203

[59] Jiang X, Kim HE, Shu H, Zhao Y, Zhang H, Kofron J, Donnelly J, Burns D, Ng SC, Rosenberg S, Wang X (2003) Distinctive roles of PHAP proteins and prothymosin-alpha in a death regulatory pathway. Science299: 223-226

[60] Jiang X, Wang X (2004) Cytochrome C-mediated apoptosis. Annu Rev Biochem73: 87-106

[61] Jost PJ, Grabow S, Gray D, McKenzie MD, Nachbur U, Huang DC, Bouillet P, Thomas HE, Borner C, Silke J (2009) XIAP discriminates between type I and type II FAS-induced apoptosis. Nature460: 1035-1039

[62] Kamada S, Shimono A, Shinto Y, Tsujimura T, Takahashi T, Noda T, Kitamura Y, Kondoh H, Tsujimoto Y (1995) bcl-2 deficiency in mice leads to pleiotropic abnormalities: accelerated lymphoid cell death in thymus and spleen, polycystic kidney, hair hypopigmentation, and distorted small intestine. Cancer Res55: 354-359

[63] Katagiri N, Shobuike T, Chang B, Kukita A, Miyamoto H (2012) The human apoptosis inhibitor NAIP induces pyroptosis in macrophages infected with Legionella pneumophila. Microbes Infect14: 1123-1132

[64] Kerr JF (2002) History of the events leading to the formulation of the apoptosis concept. Toxicology181-182: 471-474

[65] Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer26: 239-257

[66] Kim HE, Du F, Fang M, Wang X (2005) Formation of apoptosome is initiated by cytochrome c-induced dATP hydrolysis and subsequent nucleotide exchange on Apaf-1. Proc Natl Acad Sci USA102: 17545-17550

[67] Kim HE, Jiang X, Du F, Wang X (2008) PHAPI, CAS, andHsp70 promote apoptosome formation by preventing Apaf-1 aggregation and enhancing nucleotide exchange on Apaf-1. Mol Cell30: 239-247

[68] Kuida K, Zheng TS, Na S, Kuan C, Yang D, Karasuyama H, Rakic P, Flavell RA (1996) Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature384: 368-372

[69] Kuida K, Haydar TF, Kuan CY, Gu Y, Taya C, Karasuyama H, Su MS, Rakic P, Flavell RA (1998) Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell94: 325-337

[70] Kuranaga E, Miura M (2007) Nonapoptotic functions of caspases: caspases as regulatory molecules for immunity and cell-fate determination. Trends Cell Biol17: 135-144

[71] LaCasse EC, Baird S, Korneluk RG, MacKenzie AE (1998) The inhibitors of apoptosis (IAPs) and their emerging role in cancer. Oncogene17: 3247-3259

[72] Lamkanfi M, Festjens N, Declercq W, Vanden Berghe T, Vandenabeele P (2007) Caspases in cell survival, proliferation and differentiation. Cell Death Differ14: 44-55

[73] Larisch S, Yi Y, Lotan R, Kerner H, Eimerl S, Tony Parks W, Gottfried Y, Birkey Reffey S, de Caestecker MP, Danielpour D (2000) A novel mitochondrial septin-like protein, ARTS, mediates apoptosis dependent on its P-loop motif. Nat Cell Biol2: 915-921

[74] Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell91: 479-489

[75] Li H, Zhu H, Xu CJ, Yuan J (1998) Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell94: 491-501

[76] Li L, Thomas RM, Suzuki H, De Brabander JK, Wang X, Harran PG (2004) A small molecule Smac mimic potentiates TRAIL- and TNFalpha-mediated cell death. Science305: 1471-1474

[77] Li Z, Jo J, Jia JM, Lo SC, Whitcomb DJ, Jiao S, Cho K, Sheng M (2010) Caspase-3 activation via mitochondria is required for longterm depression and AMPA receptor internalization. Cell141: 859-871

[78] Li J, McQuade T, Siemer AB, Napetschnig J, Moriwaki K, Hsiao YS, Damko E, Moquin D, Walz T, McDermott A (2012) The RIP1/ RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell150: 339-350

[79] Lieber J, Eicher C, Wenz J, Kirchner B, Warmann SW, Fuchs J, Armeanu-Ebinger S (2011) The BH3 mimetic ABT-737 increases treatment efficiency of paclitaxel against hepatoblastoma. BMC Cancer11: 362

[80] Lindsten T, Ross AJ, King A, Zong WX, Rathmell JC, Shiels HA, Ulrich E, Waymire KG, Mahar P, Frauwirth K (2000) The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell6: 1389-1399

[81] Linkermann A, Green DR (2014) Necroptosis. N Engl J Med370: 455-465

[82] Liu X, Kim CN, Yang J, Jemmerson R, Wang X (1996) Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell86: 147-157

[83] Liu Z, Sun C, Olejniczak ET, Meadows RP, Betz SF, Oost T, Herrmann J, Wu JC, Fesik SW (2000) Structural basis for binding of Smac/ DIABLO to the XIAP BIR3 domain. Nature408: 1004-1008

[84] Lu J, Bai L, Sun H, Nikolovska-Coleska Z, McEachern D, Qiu S, Miller RS, Yi H, Shangary S, Sun Y (2008) SM-164: a novel, bivalent Smac mimetic that induces apoptosis and tumor regression by concurrent removal of the blockade of cIAP-1/2 and XIAP. Cancer Res68: 9384-9393

[85] Luo X, Budihardjo I, Zou H, Slaughter C, Wang X (1998) Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell94: 481-490

[86] MacFarlane M, Merrison W, Bratton SB, Cohen GM (2002) Proteasome-mediated degradation of Smac during apoptosis: XIAP promotes Smac ubiquitination in vitro. J Biol Chem277: 36611-36616

[87] Mahadevan D, Chalasani P, Rensvold D, Kurtin S, Pretzinger C, Jolivet J, Ramanathan RK, Von Hoff DD, Weiss GJ (2013) Phase I trial of AEG35156 an antisense oligonucleotide to XIAP plus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma. Am J Clin Oncol36: 239-243

[88] Martins LM, Iaccarino I, Tenev T, Gschmeissner S, Totty NF, Lemoine NR, Savopoulos J, Gray CW, Creasy CL, Dingwall C (2002) The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif. J Biol Chem277: 439-444

[89] Martins LM, Morrison A, Klupsch K, Fedele V, Moisoi N, Teismann P, Abuin A, Grau E, Geppert M, Livi GP (2004) Neuroprotective role of the Reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice. Mol Cell Biol24: 9848-9862

[90] Martins CP, Brown-Swigart L, Evan GI (2006) Modeling the therapeutic efficacy of p53 restoration in tumors. Cell127: 1323-1334

[91] McIlwain DR, Berger T, Mak TW (2013) Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol5: a008656

[92] Michaelidis TM, Sendtner M, Cooper JD, Airaksinen MS, Holtmann B, Meyer M, Thoenen H (1996) Inactivation of bcl-2 results in progressive degeneration of motoneurons, sympathetic and sensory neurons during early postnatal development. Neuron17: 75-89

[93] Mizutani Y, Nakanishi H, Li YN, Matsubara H, Yamamoto K, Sato N, Shiraishi T, Nakamura T, Mikami K, Okihara K (2007) Overexpression of XIAP expression in renal cell carcinoma predicts a worse prognosis. Int J Oncol30: 919-925

[94] Motoyama N, Wang F, Roth KA, Sawa H, Nakayama K, Negishi I, Senju S, Zhang Q, Fujii S (1995) Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science267: 1506-1510

[95] Motoyama N, Kimura T, Takahashi T, Watanabe T, Nakano T (1999) bcl-x prevents apoptotic cell death of both primitive and definitive erythrocytes at the end of maturation. J Exp Med189: 1691-1698

[96] Moulin M, Anderton H, Voss AK, Thomas T, Wong WW, Bankovacki A, Feltham R, Chau D, Cook WD, Silke J (2012) IAPs limit activation of RIP kinases by TNF receptor 1 during development. EMBO J31: 1679-1691

[97] Newton K, Dugger DL, Wickliffe KE, Kapoor N, de Almagro MC, Vucic D, Komuves L, Ferrando RE, French DM, Webster J (2014) Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science343: 1357-1360

[98] Nikolaev A, McLaughlin T, O’Leary DD, Tessier-Lavigne M (2009) APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature457: 981-989

[99] Oberst A, Dillon CP, Weinlich R, McCormick LL, Fitzgerald P, Pop C, Hakem R, Salvesen GS, Green DR (2011) Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis. Nature471: 363-367

[100] Okada H, Suh WK, Jin J, Woo M, Du C, Elia A, Duncan GS, Wakeham A, Itie A, Lowe SW (2002) Generation and characterization of Smac/DIABLO-deficient mice. Mol Cell Biol22: 3509-3517

[101] Okada H, Bakal C, Shahinian A, Elia A, Wakeham A, Suh WK, Duncan GS, Ciofani M, Rottapel R, Zuniga-Pflucker JC (2004) Survivin loss in thymocytes triggers p53-mediated growth arrest and p53-independent cell death. J Exp Med199: 399-410

[102] Oliner JD, Kinzler KW, Meltzer PS, George DL, Vogelstein B (1992) Amplification of a gene encoding a p53-associated protein in human sarcomas.[see comment]. Nature358: 80-83

[103] Popgeorgiev N, Bonneau B, Ferri KF, Prudent J, Thibaut J, Gillet G (2011) The apoptotic regulator Nrz controls cytoskeletal dynamics via the regulation of Ca2+ trafficking in the zebrafish blastula. Dev Cell20: 663-676

[104] Provencio M, Martin P, Garcia V, Candia A, Sanchez AC, Bellas C (2010) Caspase 3a: new prognostic marker for diffuse large B-cell lymphoma in the rituximab era. Leuk Lymphoma51: 2021-2030

[105] Ren J, Shi M, Liu R, Yang QH, Johnson T, Skarnes WC, Du C (2005) The Birc6 (Bruce) gene regulates p53 and the mitochondrial pathway of apoptosis and is essential for mouse embryonic development. Proc Natl Acad Sci USA102: 565-570

[106] Ren D, Tu HC, Kim H, Wang GX, Bean GR, Takeuchi O, Jeffers JR, Zambetti GP, Hsieh JJ, Cheng EH (2010) BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death program. Science330: 1390-1393

[107] Reuland SN, Goldstein NB, Partyka KA, Cooper DA, Fujita M, Norris DA, Shellman YG (2011) The combination of BH3-mimetic ABT-737 with the alkylating agent temozolomide induces strong synergistic killing of melanoma cells independent of p53. PloS One6: e24294

[108] Riedl SJ, Li W, Chao Y, Schwarzenbacher R, Shi Y (2005) Structure of the apoptotic protease-activating factor 1 bound to ADP. Nature434: 926-933

[109] Rodriguez J, Lazebnik Y (1999) Caspase-9 and APAF-1 form an active holoenzyme. Genes Dev13: 3179-3184

[110] Rolland SG, Conradt B (2010) New role of the BCL2 family of proteins in the regulation of mitochondrial dynamics. Curr Opin Cell Biol22: 852-858

[111] Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC (1997) The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases. Embo J16: 6914-6925

[112] Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH, Peter ME (1998) Two CD95 (APO-1/ Fas) signaling pathways. EMBO J17: 1675-1687

[113] Schimmer AD, Estey EH, Borthakur G, Carter BZ, Schiller GJ, Tallman MS, Altman JK, Karp JE, Kassis J, Hedley DW (2009) Phase I/II trial of AEG35156 X-linked inhibitor of apoptosis protein antisense oligonucleotide combined with idarubicin and cytarabine in patients with relapsed or primary refractory acute myeloid leukemia. J Clin Oncol27: 4741-4746

[114] Selivanova G, Iotsova V, Okan I, Fritsche M, Strom M, Groner B, Grafstrom RC, Wiman KG (1997) Restoration of the growth suppression function of mutant p53 by a synthetic peptide derived from the p53 C-terminal domain. Nat Med3: 632-638

[115] Shangary S, Qin D, McEachern D, Liu M, Miller RS, Qiu S, Nikolovska-Coleska Z, Ding K, Wang G, Chen J (2008) Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proc Natl Acad Sci USA105: 3933-3938

[116] Shchors K, Persson AI, Rostker F, Tihan T, Lyubynska N, Li N, Swigart LB, Berger MS, Hanahan D, Weiss WA (2013) Using a preclinicalmousemodel of high-grade astrocytomato optimize p53 restoration therapy. Proc Natl Acad Sci USA110: E1480-E1489

[117] Skoufias DA, Mollinari C, Lacroix FB, Margolis RL (2000) Human survivin is a kinetochore-associated passenger protein. J Cell Biol151: 1575-1582

[118] Speliotes EK, Uren A, Vaux D, Horvitz HR (2000) The survivin-like C. elegans BIR-1 protein acts with the Aurora-like kinase AIR-2 to affect chromosomes and the spindle midzone. Mol Cell6: 211-223

[119] Steinhart L, Belz K, Fulda S (2013) Smac mimetic and demethylating agents synergistically trigger cell death in acute myeloid leukemia cells and overcome apoptosis resistance by inducing necroptosis. Cell Death Dis4: e802

[120] Strater J, Herter I, Merkel G, Hinz U, Weitz J, Moller P (2010) Expression and prognostic significance of APAF-1, caspase-8 and caspase-9 in stage II/III colon carcinoma: caspase-8 and caspase-9 is associated with poor prognosis. Int J Cancer127: 873-880

[121] Sun XM, Bratton SB, Butterworth M, MacFarlane M, Cohen GM (2002) Bcl-2 and Bcl-xL inhibit CD95-mediated apoptosis by preventing mitochondrial release of Smac/DIABLO and subsequent inactivation of X-linked inhibitor-of-apoptosis protein. J Biol Chem277: 11345-11351

[122] Sun L, Wang H, Wang Z, He S, Chen S, Liao D, Wang L, Yan J, Liu W, Lei X (2012) Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell148: 213-227

[123] Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K, Takahashi R (2001) A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol Cell8: 613-621

[124] Tait SW, Green DR (2010) Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol11: 621-632

[125] Tait SW, Parsons MJ, Llambi F, Bouchier-Hayes L, Connell S, Munoz-Pinedo C, Green DR (2010) Resistance to caspaseindependent cell death requires persistence of intact mitochondria. Dev Cell18: 802-813

[126] Tamm I, Kornblau SM, Segall H, Krajewski S, Welsh K, Kitada S, Scudiero DA, Tudor G, Qui YH, Monks A (2000) Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. Clin Cancer Res6: 1796-1803

[127] Taylor RC, Cullen SP, Martin SJ (2008) Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol9: 231-241

[128] Thornberry NA, Lazebnik Y (1998) Caspases: enemies within. Science281: 1312-1316

[129] Toledo F, Wahl GM (2007) MDM2 and MDM4: p53 regulators as targets in anticancer therapy. Int J Biochem Cell Biol39: 1476-1482

[130] Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, Johnson EF, Marsh KC, Mitten MJ, Nimmer P (2008) ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res68: 3421-3428

[131] Tsujimoto Y, Cossman J, Jaffe E, Croce CM (1985) Involvement of the bcl-2 gene in human follicular lymphoma. Science228: 1440-1443

[132] Twiddy D, Cain K (2007) Caspase-9 cleavage, do you need it? Biochem J405: e1-e2

[133] Uren AG, Wong L, Pakusch M, Fowler KJ, Burrows FJ, Vaux DL, Choo KH (2000) Survivin and the inner centromere protein INCENP show similar cell-cycle localization and gene knockout phenotype. Curr Biol10: 1319-1328

[134] van Loo G, van Gurp M, Depuydt B, Srinivasula SM, Rodriguez I, Alnemri ES, Gevaert K, Vandekerckhove J, Declercq W, Vandenabeele P (2002) The serine protease Omi/HtrA2 is released from mitochondria during apoptosis. Omi interacts with caspase-inhibitor XIAP and induces enhanced caspase activity. Cell Death Differ9: 20-26

[135] Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science303: 844-848

[136] Vaux DL, Cory S, Adams JM (1988) Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature335: 440-442

[137] Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, Newman J, Reczek EE, Weissleder R, Jacks T (2007) Restoration of p53 function leads to tumour regression in vivo. Nature445: 661-665

[138] Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ, Vaux DL (2000) Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell102: 43-53

[139] Verhagen AM, Silke J, Ekert PG, Pakusch M, Kaufmann H, Connolly LM, Day CL, Tikoo A, Burke R, Wrobel C (2002) HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins. J Biol Chem277: 445-454

[140] Villunger A, Labi V, Bouillet P, Adams J, Strasser A (2011) Can the analysis of BH3-only protein knockout mice clarify the issue of ‘direct versus indirect’ activation of Bax and Bak? Cell Death Differ18: 1545-1546

[141] Vucic D, Kaiser WJ, Harvey AJ, Miller LK (1997) Inhibition of reaperinduced apoptosis by interaction with inhibitor of apoptosis proteins (IAPs). Proc Natl Acad Sci USA94: 10183-10188

[142] Vucic D, Kaiser WJ, Miller LK (1998) Inhibitor of apoptosis proteins physically interact with and block apoptosis induced by Drosophila proteins HID and GRIM. Mol Cell Biol18: 3300-3309

[143] Vucic D, Stennicke HR, Pisabarro MT, Salvesen GS, Dixit VM (2000) ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas. Curr Biol10: 1359-1366

[144] Wade M, Wang YV, Wahl GM (2010) The p53 orchestra: Mdm2 and Mdmx set the tone. Trends Cell Biol20: 299-309

[145] Wang SL, Hawkins CJ, Yoo SJ, Muller HA, Hay BA (1999) The Drosophila caspase inhibitor DIAP1 is essential for cell survival and is negatively regulated by HID. Cell98: 453-463

[146] Wang Y, Suh YA, Fuller MY, Jackson JG, Xiong S, Terzian T, Quintas-Cardama A, Bankson JA, El-Naggar AK, Lozano G (2011) Restoring expression of wild-type p53 suppresses tumor growth but does not cause tumor regression in mice with a p53 missense mutation. J Clin Investig121: 893-904

[147] Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB, Korsmeyer SJ (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science292: 727-730

[148] White K, Tahaoglu E, Steller H (1996) Cell killing by the Drosophila gene reaper. Science271: 805-807

[149] Woo M, Hakem R, Soengas MS, Duncan GS, Shahinian A, Kagi D, Hakem A, McCurrach M, Khoo W, Kaufman SA (1998) Essential contribution of caspase 3/CPP32 to apoptosis and its associated nuclear changes. Genes Dev12: 806-819

[150] Woo M, Hakem R, Furlonger C, Hakem A, Duncan GS, Sasaki T, Bouchard D, Lu L, Wu GE, Paige CJ (2003) Caspase-3 regulates cell cycle in B cells: a consequence of substrate specificity. Nat Immunol4: 1016-1022

[151] Wu G, Chai J, Suber TL, Wu JW, Du C, Wang X, Shi Y (2000) Structural basis of IAP recognition by Smac/DIABLO. Nature408: 1008-1012

[152] Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW (2007) Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature445: 656-660

[153] Yang QH, Du C (2004) Smac/DIABLO selectively reduces the levels of c-IAP1 and c-IAP2 but not that of XIAP and livin in HeLa cells. J Biol Chem279: 16963-16970

[154] Yang QH, Church-Hajduk R, Ren J, Newton ML, Du C (2003) Omi/ HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis. Genes Dev17: 1487-1496

[155] Yin XM, Wang K, Gross A, Zhao Y, Zinkel S, Klocke B, Roth KA, Korsmeyer SJ (1999) Bid-deficient mice are resistant to Fasinduced hepatocellular apoptosis. Nature400: 886-891

[156] Yoshida H, Kong YY, Yoshida R, Elia AJ, Hakem A, Hakem R, Penninger JM, Mak TW (1998) Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell94: 739-750

[157] Yu T, Wang X, Purring-Koch C, Wei Y, McLendon GL (2001) A mutational epitope for cytochrome C binding to the apoptosis protease activation factor-1. J Biol Chem276: 13034-13038

[158] Yu X, Vazquez A, Levine AJ, Carpizo DR (2012) Allele-specific p53 mutant reactivation. Cancer Cell21: 614-625

[159] Zermati Y, Garrido C, Amsellem S, Fishelson S, Bouscary D, Valens F, Varet B, Solary E, Hermine O (2001) Caspase activation is required for terminal erythroid differentiation. J Exp Med193: 247-254

[160] Zermati Y, Mouhamad S, Stergiou L, Besse B, Galluzzi L, Boehrer S, Pauleau AL, Rosselli F, D’Amelio M, Amendola R (2007) Nonapoptotic role for Apaf-1 in the DNA damage checkpoint: 624-637

[161] Zhang HZ, Kasibhatla S, Wang Y, Herich J, Guastella J, Tseng B, Drewe J, Cai SX (2004) Discovery, characterization and SAR of gambogic acid as a potent apoptosis inducer by a HTS assay. Bioorg Med Chem12: 309-317

[162] Zhang DW, Shao J, Lin J, Zhang N, Lu BJ, Lin SC, Dong MQ, Han J (2009) RIP3, an energy metabolism regulator that switches TNFinduced cell death from apoptosis to necrosis. Science325: 332-336

[163] Zlobec I, Steele R, Terracciano L, Jass JR, Lugli A (2007) Selecting immunohistochemical cut-off scores for novel biomarkers of progression and survival in colorectal cancer. J Clin Pathol60: 1112-1116

[164] Zou H, Henzel WJ, Liu X, Lutschg A, Wang X (1997) Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell90: 405-413

[165] Zou H, Li Y, Liu X, Wang X (1999) An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem274: 11549-11556

[166] Zou H, Yang R, Hao J, Wang J, Sun C, Fesik SW, Wu JC, Tomaselli KJ, Armstrong RC (2003) Regulation of the Apaf-1/caspase-9 apoptosome by caspase-3 and XIAP. J Biol Chem278: 8091-8098

RIGHTS & PERMISSIONS

2014 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.